DOCSLIB.ORG

P53 and Ceramide As Collaborators in the Stress Response

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Int. J. Mol. Sci. 2013, 14, 4982-5012; doi:10.3390/ijms14034982

OPEN ACCESS

International Journal of

Molecular Sciences

ISSN 1422-0067

www.mdpi.com/journal/ijms

Review

p53 and Ceramide as Collaborators in the Stress Response

Rouba Hage-Sleiman 1,2,*, Maria O. Esmerian 1,2, Hadile Kobeissy 2 and Ghassan Dbaibo 1,2

1

Department of Pediatrics and Adolescent Medicine, Division of Pediatric Infectious Diseases, Faculty of Medicine, American University of Beirut, P.O. Box 11-0236 Riad El Solh, 1107 2020 Beirut, Lebanon; E-Mails: [email protected] (M.O.E.); [email protected] (G.D.)

2

Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, P.O. Box 11-0236 Riad El Solh, 1107 2020 Beirut, Lebanon; E-Mail: [email protected]

* Author to whom correspondence should be addressed; E-Mail: [email protected];
Tel.: +961-1-350-000 (ext. 4883).

Received: 26 December 2012; in revised form: 22 January 2013 / Accepted: 1 February 2013 / Published: 1 March 2013

Abstract: The sphingolipid ceramide mediates various cellular processes in response to several extracellular stimuli. Some genotoxic stresses are able to induce p53-dependent ceramide accumulation leading to cell death. However, in other cases, in the absence of the tumor suppressor protein p53, apoptosis proceeds partly due to the activity of this “tumor suppressor lipid”, ceramide. In the current review, we describe ceramide and its roles in signaling pathways such as cell cycle arrest, hypoxia, hyperoxia, cell death, and cancer. In a specific manner, we are elaborating on the role of ceramide in mitochondrial apoptotic cell death signaling. Furthermore, after highlighting the role and mechanism of action of p53 in apoptosis, we review the association of ceramide and p53 with respect to apoptosis.

Strikingly, the hypothesis for a direct interaction between ceramide and p53 is less favored.

Recent data suggest that ceramide can act either upstream or downstream of p53 protein through posttranscriptional regulation or through many potential mediators, respectively.

Keywords: ceramide; p53; apoptosis; sphingolipids; mitochondria; signaling; Bcl2 family; caspase

Int. J. Mol. Sci. 2013, 14

4983
1. Introduction

Ceramide is a key sphingolipid that acts as a second messenger for multiple extracellular stimuli to mediate many cellular processes. Ceramide signaling, conserved throughout evolution, was found to be involved in death signaling in many systems. Since yeast cells undergo a cell death mechanism that resembles apoptosis, the sphingomyelin pathway appears evolutionarily older than the caspase-mediated death programs described in higher organisms [1]. Most DNA damaging agents and genotoxic stressors induce apoptosis in p53-dependent pathways. However, in the absence of p53, programmed cell death proceeds and is partly mediated by the “tumor suppressor lipid”, ceramide. Nevertheless, many stimuli can cause p53-dependent ceramide accumulation leading to cell death. In this review, we intend to focus on the role of ceramide in signaling pathways of apoptosis and try to shed light on its relation with p53.

2. Ceramide Biosynthesis

Ceramide is an N-acylsphingosine consisting of a fatty acid bound to the amino group of the sphingoid base, sphingosine. In general, ceramides are usually found with mono-unsaturated or saturated fatty acids of various lengths that significantly alter their physical properties. Many natural ceramides are being isolated and might be of therapeutic importance such as cameroonemide A from the plant Helichrysum cameroonense [2] and ceramide/cerebroside from the stem bark of Ficus mucuso [3]. Ceramides with 16–24 carbon fatty acyl chains are the most commonly found in mammalian cellular membranes. Depending on the cell type and stimulus, ceramide is generated by three major pathways (Figure 1). First, in the cell membrane, sphingomyelin can be broken down to ceramide in a reaction catalyzed by sphingomyelinases (neutral, acidic, or alkaline). Second, the de novo synthesis of ceramide occurs by the condensation of palmitate and serine to form 3-keto-dihydrosphingosine that is further reduced to dihydrosphingosine. This pathway, generating ceramide from less complex molecules, is catalyzed by the enzyme serine palmitoyl transferase (SPT) and occurs in the endoplasmic reticulum (ER). Dihydrosphingosine is then acylated by the enzyme (dihydro) ceramide synthase (CerS) of which there are 6 isoforms (CerS1-6) to produce dihydroceramide [4]. In its turn, dihydroceramide is then converted to ceramide by the dihydroceramide desaturase enzyme and transported to the Golgi by either vesicular trafficking or by

the ceramide transfer protein CERT [5]. Endoplasmic reticulum–trans-Golgi membrane contacts are required for nonvesicular ceramide transport. These contact sites facilitate the transfer of newly synthesized ceramide from ER to sphingomyelin synthase (SMS) located at the trans-Golgi via CERT [5].

The third pathway is termed the salvage pathway. It contributes from 50% to 90% of sphingolipid biosynthesis, and occurs through the breakdown of complex sphingolipids and glycosphingolipids in acidic cellular compartments such as the late endosomes and lysosomes, to produce sphingosine. For instance, sphingomyelin can be converted to ceramide by acid sphingomyelinase, encoded by a distinct gene than that of neutral sphingomyelinase [6]. Furthermore, ceramide can be hydrolyzed by acid ceramidase to form sphingosine and a free fatty acid, both of which, and unlike ceramide, are able to leave the lysosome. Ceramide synthase family members probably trap free sphingosine released from the lysosome at the surface of the endoplasmic reticulum or in its associated membranes [3,4].

Int. J. Mol. Sci. 2013, 14

4984

Figure 1. Metabolic pathways of ceramide synthesis and degradation: Names of organelles (A to D) are underlined. Names of enzymes are written in italic. Black solid arrows are used to show metabolic conversions. Blue dashed arrows indicate protein-mediated transfers. Abbreviations: SPT: Serine Palmitoyltransferase; CerS: Ceramide synthase; CERT: ceramide transfer protein. SMS: sphingomyelin synthase; A-SMase: Acid Sphingomyelinase, N-SMase: Neutral sphingomyelinase; GCS: Glucosylceramide synthase.

C. Golgi
SM

SMS

SM
Ceramide

GCS
N-SMase

D. Lysosome SM

CERT

GlcCer
B. Endoplasmic

Reticulum

  • Dihydroceramide
  • Ceramide

A-SMase

Ceramide

Ceramidase
Desaturase
CerS

Dihydrosphingosine

SPT

Serine + Palmitoyl-CoA

Sphingosine
Sphingosine

Ceramidase
SMS

A. Plasma Membrane

  • Ceramide
  • SM

N-SMase

Additional studies revealed that variation in free Mg2+ causes sustained changes in membrane phospholipids and second messengers resulting in the activation of intracellular signal transcription molecules such as NF-κB, proto-oncogenes c-fos and c-jun, MAPK and MAPKK in vascular smooth muscle cells in vitro [7]. More importantly, variations in Mg2+ cause truncation of membrane fatty acids, significant activation of sphingomyelinase (SMase) and alterations in membrane sphingomyelin leading to the release of ceramides. Consequently, because of all these modifications, apoptotic caspases become activated and mitochondrial cytochrome c is released [8–10]. Furthermore, and contrary to sphingomyelinase, SMS directly regulates cellular ceramide and diacylglycerol (DAG) levels [11]. It was recently shown that Mg2+ deficiency upregulates SMS and p53 in diverse cardiovascular tissues and cells. Mg2+-deficient environments drive the de novo synthesis of ceramide via the activation of three enzymes in the sphingolipid pathway: SPT, SMS, and CerS. The lower the Mg2+ is, the greater is the synthesis of ceramide [12].
Although the cytoplasmic generated ceramide was described to play important roles in mediating signaling pathways, membrane ceramide share equivalent importance in mediating cellular pathways and functional processes. For instance, ceramide generated at the exoplasmic leaflet of the plasma membrane self-associates and mediates the formation of ceramide-rich platforms (CRPs) with diameters of 200 nm up to several microns. These macrodomains are thought to derive from

Int. J. Mol. Sci. 2013, 14

4985

sphingolipid and cholesterol-enriched rafts and seem to be active sites for protein oligomerization during transmembrane signaling [13]. However, some exceptions exist where membrane ceramide does not participate in signaling. For instance, in the breast cancer cell line MCF7, ceramide generation at the outer leaflet of the plasma membrane following the exogenous addition of bacterial sphingomyelinase does not induce cell death [14–16].

3. Ceramide and Cellular Signaling

Ceramide accumulates under specific conditions to play an important role in signaling pathways.
Indeed, ceramide is a topological cell-signaling lipid that forms functionally distinct endomembrane structures and vesicles termed “sphingosome” that organize into a specialized apical compartment in polarized cells [17]. In general, growth factors, chemical agents, and environmental stresses generate ceramide in order to mediate proliferation, membrane receptor functions, immune inflammatory responses, differentiation, cell adhesion, growth arrest, or apoptosis [6,12,18–20]. Furthermore, there is evidence that ceramide mediates another terminal cellular event, senescence [21]. Indeed, ceramide contributes to senescence by activating the growth suppressor pathway through retinoblastoma (Rb) dephosphorylation and the mitogenic pathway mediated by c-Fos and AP-1 [22]. Moreover, ceramide can regulate other cellular mechanisms such as phagocytosis and autophagy. First, permeable C(6)-ceramide increases the cellular levels of endogenous ceramides via a sphingosine-recycling pathway leading to enhanced phagocytosis by Kupffer cell [23]. Second, MCF7 cells deficient in autophagy protein that were sensitive to photodynamic therapy presented an increase in ceramide levels [24]. In some cases, inhibiting the ceramide apoptotic pathway may lead to autophagy. For example, prostate cancer cell lines overexpressing acid ceramidase (AC) are resistant to ceramide-induced apoptosis because of the conversion of ceramide to sphingosine and consequently to the antiapoptotic sphingosine 1-phosphate. These cells were also found to have increased lysosomal density and increased levels of autophagy [25].
In addition to all the previously described roles, ceramide is involved in vesicular transport systems.
Under normal physiological conditions, the binding of transferrin to its receptor generates ceramide at the cell surface through the activation of acid sphingomyelinase [26]. Ceramide self-assembles into domains that laterally sort transferrin receptors to clathrin-coated pits for endocytosis [26]. It was shown that in the absence of ceramide, lipid rafts take over to complete some mechanims. Under abnormal conditions where ceramide cannot be generated, transferrin/transferrin receptor complex translocates to the lipid rafts of the plasma membrane where it internalizes by clathrin-independent pathway [26]. Furthermore, in a recent study by Castro et al., it was shown that ligand-bound Fas receptors oligomerize in lipid rafts independent of ceramide [27].

3.1. Ceramide and Hypoxia/Hyperoxia

Both hypoxia and hyperoxia are common stressors to which human and animal cells are exposed in the course of diseases and their treatment. Many studies were conducted to determine the effects of hypoxia or hyperoxia on ceramide. First, it was shown that upon exposure to chronic hypoxia, the myocardial mass was increased in a rat and mouse models of cyanotic congenital heart disease due to compensatory cardiac proliferation in the right ventricle (RV) [28,29]. This phenotype was

Int. J. Mol. Sci. 2013, 14

4986

associated with the absence of apoptosis, the relative decrease in total ceramide, specifically N-palmitoyl-D-erythro-sphingosine (C16-Cer) levels [30], and the significant increase of the precursor dihydro-N-palmitoyl-D-erythro-sphinganine (DHC16) in the RV. These findings suggested that dihydroceramide, and not only ceramide, plays a role in the RV adaptive response to hypoxia manifested by the survival of rat and mouse cardiomyocytes [29]. Studies in cultured cells exposed to hypoxia yielded different results compared to animal models. In a recent study done on H-SY5Y neuroblastoma cells, it was shown that hypoxia increased the ceramide concentration through de novo pathway and subsequently apoptosis was induced, with DNA fragmentation and ADP-ribose polymerase (PARP) cleavage [31]. In another study, the effect of hyperoxia was investigated on neonatal rat lung. It was shown that exposure to short term hyperoxia (3 days) induced apoptosis despite the increase in Bcl-2 through de novo synthesis of ceramide and overexpression of Bax. After 7 days of hyperoxia, animals adapted and survived the high oxygen levels by returning ceramide to baseline levels and reducing Bax and Bcl-2. However, prolonged hyperoxia (14 days) resulted in acute lung injury and absence of apoptosis despite the rise observed in Bax and ceramide levels probably because of a concomitant increase in the expression of Bcl-2 [32].

3.2. Ceramide Accumulation and Cell Death

Apoptosis occurs through either an intrinsic mitochondrial or an extrinsic death receptor pathway [33]. In the mitochondrial pathway, mitochondria are targeted either directly or through transduction by proapoptotic members of the Bcl-2 family, such as Bax and Bak. The mitochondria then release the apoptogenic protein cytochrome c leading to caspase activation and apoptosis. In the death receptor pathway, following the ligand binding, the receptors (Fas and tumor necrosis factor TNF) located at the cellular membrane recruit adaptor proteins such as Fas-Associated Death Domain (FADD) that then recruit pro-caspases, e.g., procaspase 8, which become activated upon clustering to initiate a caspase cascade. A crosstalk between both pathways is mediated via Bid, which becomes cleaved by apical caspases to target the mitochondria, and probably other still unknown factors [34].
The involvement of ceramide in apoptotic pathways has been widely studied. Sphingomyelin (SM), an immediate precursor to ceramide, is an important participant in key signal transduction pathways [35]. SM is localized mostly in the outer leaflet of the plasma membrane. Additionally, since SM gets synthesized in the cis and medial Golgi apparatus, the signaling pool of SM resides also in the inner leaflet of the plasma membrane or on the cytoplasmic face of a subcellular fraction (such as Golgi or endosomes) [36]. Indeed, many signaling lipid-regulated enzymes and lipases are associated with the inner leaflet of the plasma membrane; these include the ceramide-activated protein kinase C zeta (PKCz) [37] and ceramide-activated protein phosphatase (CAPP), as well as phospholipases C and A2 [35]. The exogenous use of bacterial sphingomyelinase allowed the examination of the role of outer leaflet sphingomyelin in inducing apoptotic signaling. Under these conditions, it was found that the generated ceramide was not enough to induce apoptotic responses [27]. The outer leaflet plasma membrane ceramide is associated with inhibition of PKC-induced nuclear factor-κB (NF-κB) activation [38], and of platelet-derived growth factor-induced phosphatidyl 3-kinase activity [39]. Thus, ceramide action appears to be compartmentalized. Indeed, when ceramide was generated endogenously by targeting bacterial sphingomyelinase to the mitochondria in MCF7 cells, it led to

Int. J. Mol. Sci. 2013, 14

4987

apoptosis marked with the death substrate poly (ADP-ribosyl) polymerase (PARP) cleavage [14]. However, when it was targeted to other compartments of the cell, no apoptosis was observed [14]. In this case, bacterial sphingomyelinase acts on both the inner and outer mitochondrial membrane pool of SM and the ceramide generated in either mitochondrial membrane can flip-flop from one leaflet to the other [7]. Furthermore, mitochondrial ceramide generation induces intrinsic apoptosis mediated by cytochrome c release. However, all these apoptotic events can be prevented by overexpression of Bcl-2s [14].
Under the same concept of implication of ceramide in cell death, several recent studies have shown that the biosynthetic pathway for ceramide generation differs depending on the type of cell and stimulus. Furthermore, depending on other cellular conditions, the generated ceramide can play dual functions inducing apoptosis or resulting in prosurvival according to its context of expression and to the cell type. For example, ionizing radiation (IR) induces de novo synthesis of ceramide and triggers HeLa cell apoptosis by specifically activating ceramide synthase isoforms 5 and 6 that preferentially generate C16 ceramide [40]. In these same cells, ceramide synthase 2 plays a protective role through the generation of C24 ceramides [40]. In another study using human monocytes U937, C16 ceramide was also shown to play an apoptotic role. Apoptosis was triggered by incubating these cells with palmitate. This resulted in an increase in cellular C16 ceramide and sphingomyelin, a decrease in reduced glutathione, and increase in reactive oxygen species (ROS) [41]. C16 ceramide was also described as crucial to induce the mitochondrial-mediated apoptosis observed in the adipose triglyceride lipase (Atgl−/−) null macrophages [42]. Contrary to these two previous studies, in squamous cell carcinomas (HNSCCs), C16 ceramide generated by CerS6 plays prosurvival antiapoptotic roles via ATF6/CHOP in response to endoplasmic reticulum-stress-induced apoptosis [43]. Similarly, C18 ceramide de novo synthesized by ceramide synthase 1 mediates the protective apoptotic response in human head and neck cancer instead of C16 ceramides in response to ER-stress and chemotherapy [44]. It was further shown that CerS1 gets cleaved and translocated from the endoplasmic reticulum to the Golgi apparatus with the help of protein kinase C in order to generate these ceramides [45]. All these findings shed light on the significance of the species of ceramide that is generated mediating a different cellular response according to the cell and stimulus types respectively.
In addition to de novo synthesis, ceramide can be generated by the sphingomyelinase pathways in response to apoptotic stimuli. This was shown in mitochondria of aged hearts where ceramide accumulated via the hydrolysis of sphingomyelin by neutral sphingomyelinase (N-SMase) [46]. In other cases, both pathways can be used simultaneously. For instance, in melanoma, interleukin-24 induces an ER stress triggered apoptotic response via the de novo synthesis of ceramide and acid sphingomyelinase (A-SMase) activity. In this context, activated protein phosphatase 2A (PP2A) was described to act downstream of the generated ceramide (Figure 2) contributing to apoptosis by dephosphorylation of antiapoptotic Bcl-2 and the Bcl-2 kinase PKCα [47].
Ceramide accumulation is often accompanied by ROS generation. In addition, ceramide can induce cell death through both caspase-dependent and caspase-independent mechanisms as described in mesenchymal stem cells derived from human adipose tissue (hASCs) [48]. Changes in endogenous levels of ceramide occur in the first stages of apoptosis such as activation of the initiator caspases, caspase 8, 9, and 10, and usually prior to the activation of the executioner caspases such as caspase 3, 6, and 7 [14]. Indeed, upon mitochondrial ceramide accumulation, cytosolic cytochrome c gets

Int. J. Mol. Sci. 2013, 14

4988

released from the mitochondria through ceramide channels [49]. In the cytosol, it forms a complex with Apaf-1 and procaspase 9, resulting in activation of caspase 9, which then activates other caspases (Figure 2), such as caspase 3, to control the execution of programmed cell death [14].

Figure 2. Mitochondrial apoptotic pathway involving p53 and ceramide in response to

stress: Ceramide activates protein phosphatase 2A (PP2A) which dephosphorylates Bcl-2 and inhibits its antiapoptotic activity. Ceramide generated in the endoplasmic reticulum translocates to the mitochondria. Additionally, another pool of ceramide can be generated in the mitochondria. On the other hand, nuclear p53 activates the transcription of proapoptotic genes (Puma, Noxa, Bax and Bak). Bak elevates the activity of ceramide synthase in the mitochondrial outer membrane. Mitochondrial ceramides form large stable barrel-like channels either alone or with Bax. These channels are used to release cytochrome c to the cytoplasm resulting in activation of caspases and execution of apoptosis. Cytoplasmic p53 interacts with Bcl-xL in the mitochondria preventing it from

disassembling ceramide and Bax channels. Puma and Noxa bind to antiapoptotic Bcl-2 family proteins freeing Bax and/or Bak from them. Noxa is also involved in the mitochondrial p53 and ceramide-dependent apoptosis but the specific pathway is still unclear.

STRESS p53
Puma

Noxa
Bcl-xl

Bcl-2 p53
Bax

Bak

?

Bax Channel

?

Ceramide

PP2A

Ceramide Channel Activation

Caspases
APOPTOSIS

Recommended publications
  • Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines

    Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines

    cancers Review Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines Wei Guo, Hor-Yue Tan, Feiyu Chen, Ning Wang and Yibin Feng * School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 00000, China; [email protected] (W.G.); [email protected] (H.-Y.T.); [email protected] (F.C.); [email protected] (N.W.) * Correspondence: [email protected] Received: 22 December 2019; Accepted: 3 February 2020; Published: 10 February 2020 Abstract: Cancer is a common and complex disease with high incidence and mortality rates, which causes a severe public health problem worldwide. As one of the standard therapeutic approaches for cancer therapy, the prognosis and outcome of chemotherapy are still far from satisfactory due to the severe side effects and increasingly acquired resistance. The development of novel and effective treatment strategies to overcome chemoresistance is urgent for cancer therapy. Metabolic reprogramming is one of the hallmarks of cancer. Cancer cells could rewire metabolic pathways to facilitate tumorigenesis, tumor progression, and metastasis, as well as chemoresistance. The metabolic reprogramming may serve as a promising therapeutic strategy and rekindle the research enthusiasm for overcoming chemoresistance. This review focuses on emerging mechanisms underlying rewired metabolic pathways for cancer chemoresistance in terms of glucose and energy, lipid, amino acid, and nucleotide metabolisms, as well as other related metabolisms. In particular, we highlight the potential of traditional Chinese medicine as a chemosensitizer for cancer chemotherapy from the metabolic perspective. The perspectives of metabolic targeting to chemoresistance are also discussed.
  • Správa O Činnosti Organizácie SAV Za Rok 2013

    Správa O Činnosti Organizácie SAV Za Rok 2013

    Ústav normálnej a patologickej fyziológie SAV Správa o činnosti organizácie SAV za rok 2013 Bratislava január 2014 Obsah osnovy Správy o činnosti organizácie SAV za rok 2013 1. Základné údaje o organizácii 2. Vedecká činnosť 3. Doktorandské štúdium, iná pedagogická činnosť a budovanie ľudských zdrojov pre vedu a techniku 4. Medzinárodná vedecká spolupráca 5. Vedná politika 6. Spolupráca s VŠ a inými subjektmi v oblasti vedy a techniky 7. Spolupráca s aplikačnou a hospodárskou sférou 8. Aktivity pre Národnú radu SR, vládu SR, ústredné orgány štátnej správy SR a iné organizácie 9. Vedecko-organizačné a popularizačné aktivity 10. Činnosť knižnično-informačného pracoviska 11. Aktivity v orgánoch SAV 12. Hospodárenie organizácie 13. Nadácie a fondy pri organizácii SAV 14. Iné významné činnosti organizácie SAV 15. Vyznamenania, ocenenia a ceny udelené pracovníkom organizácie SAV 16. Poskytovanie informácií v súlade so zákonom o slobodnom prístupe k informáciám 17. Problémy a podnety pre činnosť SAV PRÍLOHY A Zoznam zamestnancov a doktorandov organizácie k 31.12.2013 B Projekty riešené v organizácii C Publikačná činnosť organizácie D Údaje o pedagogickej činnosti organizácie E Medzinárodná mobilita organizácie Správa o činnosti organizácie SAV 1. Základné údaje o organizácii 1.1. Kontaktné údaje Názov: Ústav normálnej a patologickej fyziológie SAV Riaditeľ: RNDr. Oľga Pecháňová, DrSc. Zástupca riaditeľa: MUDr. Fedor Jagla, CSc. Vedecký tajomník: RNDr. Iveta Bernátová, DrSc. Predseda vedeckej rady: RNDr. Iveta Bernátová, DrSc. Členovia snemu SAV: MUDr. Fedor Jagla, CSc., MUDr. Igor Riečanský, PhD. Adresa: Sienkiewiczova 1, 813 71 Bratislava http://www.unpf.sav.sk Tel.: 02/32296063 Fax: E-mail: [email protected] Názvy a adresy detašovaných pracovísk: nie sú Vedúci detašovaných pracovísk: nie sú Typ organizácie: Rozpočtová od roku 1953 1.2.
  • Acute and Chronic Complications

    Acute and Chronic Complications

    Uniwersytet Medyczny w Łodzi Medical University of Lodz https://publicum.umed.lodz.pl Higher Blood Glucose Variability is Associated with Increased Risk of Hypoglycemia Publikacja / Publication in Well or Poorly Controlled Type 1 or Type 2 Diabetes, Czupryniak Leszek, Borkowska Anna, Szymańska-Garbacz Elektra DOI wersji wydawcy / Published http://dx.doi.org/10.2337/db17-381-663 version DOI Adres publikacji w Repozytorium URL / Publication address in https://publicum.umed.lodz.pl/info/article/AML063ddbabfba14480a6e45b1d944e1ccd/ Repository Data opublikowania w Repozytorium 2020-08-31 / Deposited in Repository on Rodzaj licencji / Type of licence Other open licence Czupryniak Leszek, Borkowska Anna, Szymańska-Garbacz Elektra : Higher Blood Glucose Variability is Associated with Increased Risk of Hypoglycemia in Well or Cytuj tę wersję / Cite this version Poorly Controlled Type 1 or Type 2 Diabetes, Diabetes, vol. 66, no. Suppl. 1, 2017, pp. 103-104, DOI:10.2337/db17-381-663 COMPLICATIONS—HYPOGLYCEMIA COMPLICATIONS—HYPOGLYCEMIA an activating role of SAMSN1, L-triiodothyronine, IFNA4, JAK1 and mTORC1, and an inhibitory action of BDNF, POR, ESR1, CTNNB1 and ERG on the gene networks identified in our samples. Moderated Poster Discussion: Hypoglycemia—Novel Concepts Our study for the first time characterizes the transcriptional responses (Posters: 381-P to 386-P), see page 19. of the BBB compartment to recurrent hypoglycemia exposure and may help identify novel therapeutic targets to restore the impaired responses against 381‑P hypoglycemia in patients with type 1 diabetes. & Supported By: National Institutes of Health; JDRF Hypoglycemia‑Associated Autonomic Failure Is Associated with POSTERS Complications Coordinated miRNA‑mRNA Network Changes in the Ventromedial Acute and Chronic Hypothalamus & 383‑P RAHUL AGRAWAL, CASEY TAYLOR, ADRIANA VIEIRA-DE-ABREU, SIMON J.
  • PDF (Ph.D.Thesis)

    PDF (Ph.D.Thesis)

    The biological and clinical characterisation and validation of novel biomarkers in colorectal cancer Seán Fitzgerald B.Sc., M.Sc. This thesis is submitted to Dublin City University for the degree of Ph.D. July 2015 Based on research carried out at School of Biotechnology, Dublin City University, Dublin 9, Ireland. Supervisors: Professor Richard O’Kennedy Dr. Gregor Kijanka External Supervisor: Professor Elaine Kay Department of Pathology, RCSI, Beaumont Hospital. i Declaration I hereby certify that this material, which I now submit for assessment on the programme of study leading to the award of Ph.D. is entirely my own work, that I have exercised reasonable care to ensure that the work is original, and does not to the best of my knowledge breach any law of copyright, and has not been taken from the work of others save and to the extent that such work has been cited and acknowledged within the text of my work. Signed: ____________ ID No.: ___________ Date: _______ ii Acknowledgements Firstly, I would like to express my sincere gratitude and appreciation to my supervisors Prof. Richard O’Kennedy, Prof. Elaine Kay and Dr. Gregor Kijanka. This thesis would not have been possible without the expert advice and guidance that I received from each of you, both on an academic and personal level. I am especially grateful to Dr. Gregor Kijanka for his endless guidance, wisdom and friendship throughout my PhD. I would like to thank all the members of the Applied Biochemistry Group and the School of Biotechnology in DCU for their help, support and friendship over the last few years.
  • A Selective Inhibitor of Ceramide Synthase 1 Reveals a Novel Role in Fat Metabolism

    A Selective Inhibitor of Ceramide Synthase 1 Reveals a Novel Role in Fat Metabolism

    ARTICLE DOI: 10.1038/s41467-018-05613-7 OPEN A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism Nigel Turner1, Xin Ying Lim2,3, Hamish D. Toop 4, Brenna Osborne 1, Amanda E. Brandon5, Elysha N. Taylor4, Corrine E. Fiveash1, Hemna Govindaraju1, Jonathan D. Teo3, Holly P. McEwen3, Timothy A. Couttas3, Stephen M. Butler4, Abhirup Das1, Greg M. Kowalski 6, Clinton R. Bruce6, Kyle L. Hoehn 7, Thomas Fath1,10, Carsten Schmitz-Peiffer8, Gregory J. Cooney5, Magdalene K. Montgomery1, Jonathan C. Morris 4 & Anthony S. Don3,9 1234567890():,; Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology. Genetic mouse models have established C16 ceramide as a driver of insulin resistance in liver and adipose tissue. C18 ceramide, syn- thesized by ceramide synthase 1 (CerS1), is abundant in skeletal muscle and suggested to promote insulin resistance in humans. We herein describe the first isoform-specific ceramide synthase inhibitor, P053, which inhibits CerS1 with nanomolar potency. Lipidomic profiling shows that P053 is highly selective for CerS1. Daily P053 administration to mice fed a high- fat diet (HFD) increases fatty acid oxidation in skeletal muscle and impedes increases in muscle triglycerides and adiposity, but does not protect against HFD-induced insulin resis- tance. Our inhibitor therefore allowed us to define a role for CerS1 as an endogenous inhibitor of mitochondrial fatty acid oxidation in muscle and regulator of whole-body adiposity. 1 School of Medical Sciences, UNSW Sydney, Sydney 2052 NSW, Australia. 2 Prince of Wales Clinical School, Faculty of Medicine, UNSW Sydney, Sydney 2052 NSW, Australia.
  • Ceramides: Nutrient Signals That Drive Hepatosteatosis

    Ceramides: Nutrient Signals That Drive Hepatosteatosis

    J Lipid Atheroscler. 2020 Jan;9(1):50-65 Journal of https://doi.org/10.12997/jla.2020.9.1.50 Lipid and pISSN 2287-2892·eISSN 2288-2561 Atherosclerosis Review Ceramides: Nutrient Signals that Drive Hepatosteatosis Scott A. Summers Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA Received: Sep 24, 2019 ABSTRACT Revised: Nov 4, 2019 Accepted: Nov 10, 2019 Ceramides are minor components of the hepatic lipidome that have major effects on liver Correspondence to function. These products of lipid and protein metabolism accumulate when the energy needs Scott A. Summers of the hepatocyte have been met and its storage capacity is full, such that free fatty acids start Department of Nutrition and Integrative to couple to the sphingoid backbone rather than the glycerol moiety that is the scaffold for Physiology, University of Utah, 15N 2030E, Salt Lake City, UT 84112, USA. glycerolipids (e.g., triglycerides) or the carnitine moiety that shunts them into mitochondria. E-mail: [email protected] As ceramides accrue, they initiate actions that protect cells from acute increases in detergent- like fatty acids; for example, they alter cellular substrate preference from glucose to lipids Copyright © 2020 The Korean Society of Lipid and they enhance triglyceride storage. When prolonged, these ceramide actions cause insulin and Atherosclerosis. This is an Open Access article distributed resistance and hepatic steatosis, 2 of the underlying drivers of cardiometabolic diseases. under the terms of the Creative Commons Herein the author discusses the mechanisms linking ceramides to the development of insulin Attribution Non-Commercial License (https:// resistance, hepatosteatosis and resultant cardiometabolic disorders.
  • Biological Functions of Sphingomyelin Synthase Related Protein and Ceramide Synthase 4 Investigated with Transgenic Mouse Mutants

    Biological Functions of Sphingomyelin Synthase Related Protein and Ceramide Synthase 4 Investigated with Transgenic Mouse Mutants

    Biological functions of Sphingomyelin synthase related protein and Ceramide synthase 4 investigated with transgenic mouse mutants Dissertation Zur Erlangung des Doktorgrades (Dr. rer. nat.) der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn vorgelegt von Andreas Bickert aus Neuwied Bonn, 2016 Angefertigt mit Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn Erstgutachter: Prof. Dr. Klaus Willecke Zweitgutachter: Prof. Dr. Michael Hoch Tag der Promotion: 25.10.2016 Erscheinungsjahr: 2017 Table of Contents Table of Contents 1 Introduction.................................................................................................. 1 1.1 Biological lipids ............................................................................................ 1 1.2 Eucaryotic membranes ................................................................................ 3 1.3 Sphingolipids ............................................................................................... 5 1.3.1 Sphingolipid metabolic pathway ................................................................. 6 1.3.1.1 De novo sphingolipid biosynthesis .......................................................... 8 1.3.1.2 The ceramide transfer protein ................................................................. 8 1.3.1.3 Biosynthesis of complex sphingolipids .................................................... 9 1.3.1.4 Sphingolipid degradation and the salvage
  • Deutsche Nationalbibliografie

    Deutsche Nationalbibliografie

    Deutsche Nationalbibliografie Reihe H Hochschulschriften Monatliches Verzeichnis Jahrgang: 2018 H 03 Stand: 07. März 2018 Deutsche Nationalbibliothek (Leipzig, Frankfurt am Main) 2018 ISSN 1869-3989 urn:nbn:de:101-201711171596 2 Hinweise Die Deutsche Nationalbibliografie erfasst eingesandte Pflichtexemplare in Deutschland veröffentlichter Medienwerke, aber auch im Ausland veröffentlichte deutschsprachige Medienwerke, Übersetzungen deutschsprachiger Medienwerke in andere Sprachen und fremdsprachige Medienwerke über Deutschland im Original. Grundlage für die Anzeige ist das Gesetz über die Deutsche Nationalbibliothek (DNBG) vom 22. Juni 2006 (BGBl. I, S. 1338). Monografien und Periodika (Zeitschriften, zeitschriftenartige Reihen und Loseblattausgaben) werden in ihren unterschiedlichen Erscheinungsformen (z.B. Papierausgabe, Mikroform, Diaserie, AV-Medium, elektronische Offline-Publikationen, Arbeitstransparentsammlung oder Tonträger) angezeigt. Alle verzeichneten Titel enthalten einen Link zur Anzeige im Portalkatalog der Deutschen Nationalbibliothek und alle vorhandenen URLs z.B. von Inhaltsverzeichnissen sind als Link hinterlegt. In Reihe H werden die an den Hochschulen und sonsti- klassifikation (DDC) gegliedert und können auch über die gen mit Promotionsrecht ausgestatteten Körperschaften Sachgruppenlesezeichen am linken Bildschirmrand ange- Deutschlands abgenommenen Dissertationen und Habili- steuert werden. Ein direkter Sucheinstieg ist über die tationsschriften erfasst, ferner deutschsprachige Disser- entsprechende Menüfunktion möglich.
  • (12) Patent Application Publication (10) Pub. No.: US 2009/0269772 A1 Califano Et Al

    (12) Patent Application Publication (10) Pub. No.: US 2009/0269772 A1 Califano Et Al

    US 20090269772A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0269772 A1 Califano et al. (43) Pub. Date: Oct. 29, 2009 (54) SYSTEMS AND METHODS FOR Publication Classification IDENTIFYING COMBINATIONS OF (51) Int. Cl. COMPOUNDS OF THERAPEUTIC INTEREST CI2O I/68 (2006.01) CI2O 1/02 (2006.01) (76) Inventors: Andrea Califano, New York, NY G06N 5/02 (2006.01) (US); Riccardo Dalla-Favera, New (52) U.S. Cl. ........... 435/6: 435/29: 706/54; 707/E17.014 York, NY (US); Owen A. (57) ABSTRACT O'Connor, New York, NY (US) Systems, methods, and apparatus for searching for a combi nation of compounds of therapeutic interest are provided. Correspondence Address: Cell-based assays are performed, each cell-based assay JONES DAY exposing a different sample of cells to a different compound 222 EAST 41ST ST in a plurality of compounds. From the cell-based assays, a NEW YORK, NY 10017 (US) Subset of the tested compounds is selected. For each respec tive compound in the Subset, a molecular abundance profile from cells exposed to the respective compound is measured. (21) Appl. No.: 12/432,579 Targets of transcription factors and post-translational modu lators of transcription factor activity are inferred from the (22) Filed: Apr. 29, 2009 molecular abundance profile data using information theoretic measures. This data is used to construct an interaction net Related U.S. Application Data work. Variances in edges in the interaction network are used to determine the drug activity profile of compounds in the (60) Provisional application No. 61/048.875, filed on Apr.
  • Sphingolipids and Mitochondrial Dynamic

    Sphingolipids and Mitochondrial Dynamic

    cells Review Sphingolipids and Mitochondrial Dynamic Lais Brigliadori Fugio, Fernanda B. Coeli-Lacchini and Andréia Machado Leopoldino * Department of Clinical Analyses Toxicology and Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café s/n, 14040-903 Ribeirão Preto, SP, Brazil; [email protected] (L.B.F.); [email protected] (F.B.C.-L.) * Correspondence: [email protected] Received: 1 December 2019; Accepted: 27 February 2020; Published: 1 March 2020 Abstract: For decades, sphingolipids have been related to several biological functions such as immune system regulation, cell survival, and proliferation. Recently, it has been reported that sphingolipids could be biomarkers in cancer and in other human disorders such as metabolic diseases. This is evidenced by the biological complexity of the sphingolipids associated with cell type-specific signaling and diverse sphingolipids molecules. As mitochondria dynamics have serious implications in homeostasis, in the present review, we focused on the relationship between sphingolipids, mainly ceramides and sphingosine-1-phosphate, and mitochondrial dynamics directed by fission, fusion, and mitophagy. There is evidence that the balances of ceramides (C18 and C16) and S1P, as well as the location of specific ceramide synthases in mitochondria, have roles in mitophagy and fission with an impact on cell fate and metabolism. However, signaling pathways controlling the sphingolipids metabolism and their location in mitochondria need to be better understood in order to propose new interventions and therapeutic strategies. Keywords: ceramide; sphingosine; mitophagy; fission; fusion; mitochondria 1. Introduction Sphingolipids are a class of complex lipids with several functions, including membrane structure and intracellular and extracellular signaling, associated with a large number of processes.
  • Biomolecules

    Biomolecules

    biomolecules Article Ceramide Synthase 6: Comparative Analysis, Phylogeny and Evolution Roger S. Holmes 1,2,*, Keri A. Barron 2 and Natalia I. Krupenko 2,* 1 Griffith Research Institute for Drug Discovery and School of Environment and Science, Griffith University, Nathan, QLD 4111, Australia 2 Department of Nutrition, UNC-Chapel Hill, UNC Nutrition Research Institute, Kannapolis, NC 28081, USA; [email protected] * Correspondence: r.holmes@griffith.edu.au (R.S.H.); [email protected] (N.I.K.); Tel.: +61-4-1058-3348 (R.S.H.); +1-704-250-5054 (N.I.K.) Received: 30 August 2018; Accepted: 1 October 2018; Published: 8 October 2018 Abstract: Ceramide synthase 6 (CerS6, also known as LASS6) is one of the six members of ceramide synthase gene family in humans. Comparisons of CerS6 amino acid sequences and structures as well as of CerS6 gene structures/locations were conducted using data from several vertebrate genome projects. A specific role for the CerS6 gene and protein has been identified as the endoplasmic reticulum C14- and C16-ceramide synthase. Mammalian CerS6 proteins share 90–100% similarity among different species, but are only 22–63% similar to other CerS family members, suggesting that CerS6 is a distinct gene family. Sequence alignments, predicted transmembrane, lumenal and cytoplasmic segments and N-glycosylation sites were also investigated, resulting in identification of the key conserved residues, including the active site as well as C-terminus acidic and serine residues. Mammalian CerS6 genes contain ten exons, are primarily located on the positive strands and transcribed as two major isoforms. The human CERS6 gene promoter harbors a large CpG island (94 CpGs) and multiple transcription factor binding sites (TFBS), which support precise transcriptional regulation and signaling functions.
  • Ceramide Synthase 6 in Metabolic Response to Dietary Fat and Folic Acid

    Ceramide Synthase 6 in Metabolic Response to Dietary Fat and Folic Acid

    CERAMIDE SYNTHASE 6 IN METABOLIC RESPONSE TO DIETARY FAT AND FOLIC ACID Keri Anne Barron A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Nutrition in the Gillings School of Global Public Health. Chapel Hill 2020 Approved by: Natalia Krupenko Sergey Krupenko Folami Ideraabdullah Susan Smith Stephen Hursting © 2020 Keri Anne Barron ALL RIGHTS RESERVED ii ABSTRACT Keri Anne Barron: Ceramide Synthase 6 in Metabolic Response to Dietary Fat and Folic Acid (Under the direction of Natalia Krupenko) Ceramides, a class of bioactive lipids, are important regulators of cellular metabolism mediating response to nutrient stress. Recent work from our laboratory demonstrated that, in cultured cells, folate stress response is mediated by ceramide synthase 6 (CerS6), a sphingolipid enzyme producing C16-ceramide. To test the hypothesis that alterations in dietary FA will induce a CerS6-dependent response in mice, we evaluated the sphingolipid and metabolomic responses in WT and CerS6 KO mice. We also investigated the role of dietary fat in the response to folate stress in WT and KO mice. This dissertation sought to characterize the sphingolipid and metabolomic responses in wild type (WT) and CerS6 knockout (KO) mice to both short-term alterations in dietary FA as well as to long-term changes in dietary FA combined with high fat diet. As expected, CerS6 KO mice compared to WT mice exhibited significant differences in liver sphingolipids, free fatty acids and phosphatidylethanolamines, among other lipids. Inducing folate stress resulted in changes to sphingolipid pools in the liver with significantly different responses between sexes.